https://stuff.mit.edu/afs/athena/course/5/5.062/oldwww/Fall03/591.pdf

New metal complexes as potential therapeutics.

Cancer is rapidly becoming the top killer in the world. Most of the FDA approved anticancer drugs are organic molecules, while metallodrugs are very scarce. The advent of the first metal based therapeutic agent, cisplatin, launched a new era in the application of transition metal complexes for therapeutic design. Due to their unique and versatile biochemical properties, ruthenium-based compounds have emerged as promising anti-cancer agents that serve as alternatives to cisplatin and its derivertives. Ruthenium(iii) complexes have successfully been used in clinical research and their mechanisms of anticancer action have been reported in large volumes over the past few decades. Ruthenium(ii) complexes have also attracted significant attention as anticancer candidates; however, only a few of them have been reported comprehensively. In this review, we discuss the development of ruthenium(ii) complexes as anticancer candidates and biocatalysts, including arene ruthenium complexes, polypyridyl ruthenium complexes, and ruthenium nanomaterial complexes. This review focuses on the likely mechanisms of action of ruthenium(ii)-based anticancer drugs and the relationship between their chemical structures and biological properties. This review also highlights the catalytic activity and the photoinduced activation of ruthenium(ii) complexes, their targeted delivery, and their activity in nanomaterial systems.

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The development of anticancer ruthenium(II) complexes: from single molecule compounds to nanomaterials

The antitumor activity of the organometallic ruthenium(II)−arene complexes, RuCl2(η6-arene)(PTA), (arene = p-cymene, toluene, benzene, benzo-15-crown-5, 1-ethylbenzene-2,3-dimethylimidazolium tetrafluoroborate, ethyl benzoate, hexamethylbenzene; PTA = 1,3,5-triaza-7-phosphaadamantane), abbreviated RAPTA, has been evaluated. In vitro biological experiments demonstrate that these compounds are active toward the TS/A mouse adenocarcinoma cancer cell line whereas cytotoxicity on the HBL-100 human mammary (nontumor) cell line was not observed at concentrations up to 0.3 mM, which indicates selectivity of these ruthenium(II)−arene complexes to cancer cells. Analogues of the RAPTA compounds, in which the PTA ligand is methylated, have also been prepared, and these prove to be cytotoxic toward both cell lines. RAPTA-C and the benzene analogue RAPTA-B were selected for in vivo experiments to evaluate their anticancer and antimetastatic activity. The results show that these complexes can reduce the growth of lung m...

In Vitro and in Vivo Evaluation of Ruthenium(II)−Arene PTA Complexes

Organometallic chemistry, biology and medicine: ruthenium arene anticancer complexes

Ofele and Wanzlick reported the synthesis of the first N-heterocyclic carbene (NHC) metal complexes in 1968.1,2 The isolation of the first free carbene by Arduengo in 1991 set the scene for an ever-growing interest and advancement in the field of N-heterocyclic carbene chemistry.3 Shortly thereafter, the use of these ligands in organometallic chemistry, particularly in catalysis dramatically increased.4,5

N-heterocyclic carbenes are neutral 2-electron donors, with an ability to bond to both hard and soft metals making them more versatile ligands than phosphines.6 As an added advantage, not only are NHCs easier to synthesize and functionalize than phosphines but they also form a stronger bond to metals and therefore form more stable metal complexes than metal phosphine complexes.7,8 The N-heterocyclic carbene ligands interact with metal centers primarily through strong σ-donation and to a lesser degree through π-backdonation (Figure 1).9,10



Figure 1

Orbital diagram of NHC bonding to metal center.



Ghosh and coworkers11,12,13,14,15,16 as well as others17,18,19 took special interest in the exceptional stability of several metal-NHC complexes and conducted in depth analyses in order to gain better insights into the structure and bonding. In particular, the metal-ligand donor-acceptor interactions were inspected using the charge decomposition analysis (CDA). CDA is a tool used to quantitatively estimate the degree of NHC → metal σ-donation, designated by d, and NHC ← metal π-back donation, designated by b.20,21 Thus a higher d/b ratio emphasizes the ability of NHC to function as an effective σ-donor, whereas a lower d/b ratio highlights the greater NHC ← metal π-back donation. Interestingly, in the studies conducted by Ghosh, greater NHC ← metal π-back donation was observed in Pd-NHC complexes exhibiting lower d/b ratios ranging between 2.59 – 3.9913,14 and Au-NHC complexes with d/b ratios ranging between 5.23 – 5.8815,16 as compared to the Ag-NHC complexes with d/b ratios ranging between 7.8 – 12.6811,12,16. This observation could attest to why silver-NHC complexes are particularly better transmetallating agents.

The newly emerging interest in the medicinal applications of stable metal NHCs led us to examine the few accounts available in the literature dealing with this area of research. This review will discuss in detail the medicinal applications of various transition metal-NHC complexes including silver, gold, rhodium, ruthenium, and palladium. The antimicrobial, antitumor, and resistance properties, along with proposed mechanisms of action to suppress the bacterial growth or proliferation of tumor cells will be discussed.

The Medicinal Applications of Imidazolium Carbene Metal Complexes

Inhibition of the growth of the human ovarian cancer cell line A2780 by organometallic ruthenium(II) complexes of the type [(eta(6)-arene)Ru(X)(Y)(Z)], where arene is benzene or substituted benzene, X, Y, and Z are halide, acetonitrile, or isonicotinamide, or X,Y is ethylenediamine (en) or N-ethylethylenediamine, has been investigated. The X-ray crystal structures of the complexes [(eta(6)-p-cymene)Ru(en)Cl]PF(6) (5), [(eta(6)-p-cymene)RuCl(2)(isonicotinamide)] (7), and [(eta(6)-biphenyl)Ru(en)Cl]PF(6) (9) are reported. They have "piano stool" geometries with eta(6) coordination of the arene ligand. Complexes with X,Y as a chelated en ligand and Z as a monofunctional leaving group had the highest activity. Complexes 5, 6 (the iodo analogue of 5), 9, and 10 (ethylethylenediamine analogue of 9) were as active as carboplatin. Hydrolysis of the reactive Ru-Cl bond in complex 5 was detected by HPLC but was suppressed by the addition of chloride ions. Complex 5 binds strongly and selectively to G bases on DNA oligonucleotides to form monofunctional adducts. No inhibition of topoisomerase I or II by complexes 5, 6, or 9 was detected. These chelated Ru(II) arene complexes have potential as novel metal-based anticancer agents with a mechanism of action different from that of the Ru(III) complex currently on clinical trial.

Rhona E. Aird

Papers

Inhibition of cancer cell growth by ruthenium(II) arene complexes